Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network

作者：Zihan Yang, Li Zhou, Tongxu Si, Siyuan Chen, Chengxi Liu, Kelvin Kaki Ng, Zesheng Wang, Zhiji Chen, Chan Qiu, Guopan Liu, Qingliang Wang, Xiaoyu Zhou, Liang Zhang, Zhong‐Ping Yao, Song He, Mengsu Yang, Zhihang Zhou · 发表于：Molecular Cancer · 年份：2023 · DOI：10.1186/s12943-023-01727-9 · 被引用次数：27 · 研究领域：Microbial metabolism and enzyme function、Cancer Cells and Metastasis、Tissue Engineering and Regenerative Medicine

BACKGROUND: Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). These conditions create confined spaces for tumor cell migration and metastasis. The regulatory mechanism of confined migration remains unclear. METHODS: LC-MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissue. Collective migration and single cell migration microfluidic devices with 6 μm-high confined channels were designed and fabricated to mimic the in vivo confined space. 3D invasion assay was created by Matrigel and Collagen I mixture treat to adherent cells. 3D spheroid formation under various stiffness environment was developed by different substitution percentage GelMA. Immunoprecipitation was performed to pull down the LH1-binding proteins, which were identified by LC-MS. Immunofluorescent staining, FRET, RT-PCR, Western blotting, FRAP, CCK-8, transwell cell migration, wound healing, orthotopic liver injection mouse model and in vivo imaging were used to evaluate the target expression and cellular phenotype. RESULTS: Lysyl hydroxylase 1 (LH1) promoted the confined migration of cancer cells at both collective and single cell levels. In addition, LH1 enhanced cell invasion in a 3D biomimetic model and spheroid formation in stiffer environments. High LH1 expression correlated with poor prognosis of both HCC an...